Vitamin b6 intermediate



Patented Feb. 2, 1943 ,UNlTED STATES PATENT OFFICE VITAMIN Be INTERMEDIATE Gustaf ll. Carlson, Pearl River, N. Y., assignor to Lederle Laboratories, Inc., New York, N. Y., a corporation of Delaware No Drawing. Application September 26, 1941,

Serial No. 412,430

3 Claims.

NO ON The reactions which take place in my process may be represented as follows:

C O OCaHr C ONH:

CN CN NH: n-n. OHKN 0 CHKN O P001: or other dehydrating agent The invention will be illustrated in more detail in conjunction with the following specific examples.

Preparation of the amide of 3-cyano-4-oarbomy-6-methyl pyridone-Z Two hundred grams of the ethyl ester of 3- cyano-l-carboxy-G-methyl pyridone-Z (prepared according to the method described by Bardhan, J. C. 8., 2223 (1929)) were added to 3.5 liters of absolute methanol saturated at 0 C. with gaseous ammonia and, after 7 days at 0 C., the filtered solution was concentrated in vacuo to a small volume to give the amide of 3-cyano-4- carboxy-G-methyl pyridone-2, which melted above 300 C. with decomposition. The compound so prepared is useful as an intermediate in the synthesis of vitamin B8.

In the foregoing specific example the ethyl ester of 3-cyano-4-carboxy-6-methy1 pyridone-2 was employed in carrying out the reaction and is the preferred ester because of its cheapness and availability. It should be understood, however, that the ethyl ester may be replaced by other suitable esters of 3-cyano-4-carboxy-6- methyl pyridone-2. Among the various esters that may be employed are the alkyl esters such as methyl, propyl, amyl, hexyl, and the like. The aromatic esters, such as phenyl and naphthyl, may similarly be employed. Esters of the aralkyl type which may be satisfactory are those such I as benzyl ester and the ester of 2-hydroxymethylnaphthalene, cinnamyl alcohol, etc. The esters derived from cycloaliphatic alcohols such as cyclohexanol, methyl cyclohexanol, fenchol or fenchyl alcohol, and the like, may be employed. The use of the various other esters such as those derived from heterocyclic alcohols, such as furfuryl alcohol, tetrahydrofurfuryl alcohol or those derived from nitrol alcohols such as 2-nitro-2- methyl-l-propanol are not precluded from the present invention.

Preparation of 3,4-dicyano-6-methyl pyridone-Z Dehydration of the amide oi 3-cyano-4-carboxy-fi-methyl pyridone-2 was eflected by treatment with phosphorous oxychloride, both without the use of a solvent and in hot toluene solution. The details of a typical experiment in which no solvent was used are given herewith. The amide (2 g.) and 25 cc. of phosphorous oxychloride were heated in a bath at 1.45-150" C. for 50 minutes, excess phosphorous oxychloride was distilled in vacuo and the residue was treated with 50 g. of cracked ice. The crystalline product was filtered oil and recrystallized from aqueous alcohol. The pure dinitrile (0.4 g.) melted at 241-243 C. (uncorrected).

In subsequent experiments it was'found to be advantageous to employ an inert diluent in the reaction mixture and typical of such a dehydration are the following details. A mechanically stirred mixture of 50 g. of the amide, 250 cc. of dry toluene and 250 cc, of phosphorous oxychloride was heated in a bath at -135 C. for 9.5 hours and, after 15 hours at room temperature, the undissolved material was filtered oil and thoroughly extracted with toluene and ether. The solid was then extracted with acetone and yielded 8.9 g. of unchanged amide. The original toluene filtrate and the combined toluene and ether extracts were evaporated in vacuo and the residual product was treated with 20 cc. of ice water. The crude yellow mixture was diluted with 800 cc. of hot acetone, the insoluble product was filtered off and twice extracted with 300 cc. of hot acetone and yielded 11.: s. of recovered amide. The aqueous acetone nitrate and the combined acetone extracts were concentrated in vacuo to a. small volume and yielded 13.4 a, or the crude dinitrile (M. P. 239-243 c.) which melted at 241-242 C. alter recrystallization (meltin: points uncorrected).

Phosphorous oxychloride is the preferred dehydrating reagent in carrying out the above reaction. It should be understood, however, that any other suitable dehydrating agent may be employed. Similarly. various other inert solvents may be used to replace toluene.

Preparation of 3,4-dicyano-5-nitro-d-methyl pyridone-Z A suspension of 3,4-dicyano-6-methyl pyridone-2 (3.8 g.) in 20 cc. of acetic anhydride was treated at 45-52" C. with a solution prepared from 3 cc. of :Iumlng nitric acid, 3 cc. of acetic anhygo dride and a few crystals of urea. The resulting solution was poured onto cracked ice and yielded 2.6 g. or the crude nitro compound. The solid was dissolved in 73 cc. of acetone, the solution was treated with active charcoal and the filtered g5 soluticnwasconcentratedinvacuotoasmall volume. The solution was rapidly diluted with ether and the precipitated product was recrystallined irom an acetone-ether aolution. The pure 5 nitro derivative (1.6 a.) which was obtained had a meltina point of 242-244 c. uncorrected.

I claim:

1. The process which comprises nitration of 3,4-dicyano-8-methyl pyridone-I to rorm'eA-eicyano-ii-nitro-B-methyl pyridone-2.

16 3. The compound of the iormnla:

no 1r GUB'I'AP H. CARLSON. 

